Renal cell carcinoma‐infiltrating natural killer cells express differential repertoires of activating and inhibitory receptors and are inhibited by specific HLA class I allotypes

• Published in: International journal of cancer Vol. 106; no. 6; pp. 905 - 912
• Main Authors: Schleypen, Julia S., von Geldern, Marion, Weiß, Elisabeth H., Kotzias, Nicole, Rohrmann, Karl, Schendel, Dolores J., Falk, Christine S., Pohla, Heike
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 10.10.2003; Wiley-Liss
• Subjects: Antigens, CD - metabolism; Biological and medical sciences; Carcinoma, Renal Cell - immunology; Carcinoma, Renal Cell - pathology; Cytotoxicity, Immunologic; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - pharmacology; HLA Antigens - metabolism; Humans; Interleukin-2 - metabolism; Isoantigens - immunology; Isoantigens - pharmacology; Kidney Neoplasms - immunology; Kidney Neoplasms - pathology; Kidneys; killer cell inhibitory receptors; Killer Cells, Lymphokine-Activated - immunology; Killer Cells, Natural - immunology; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; major histocompatibility complex; Medical sciences; natural killer cells; Nephrology. Urinary tract diseases; NK receptors; Receptors, Immunologic - metabolism; renal cell carcinoma; Tumors of the urinary system; tumor‐infiltrating lymphocytes; Kidney disease; Human; HLA-System; Urinary system disease; Carcinoma; Immune response; Major histocompatibility system; Cellular immunity; Tumor infiltrating lymphocyte; Malignant tumor; Kidney; Natural killer cell; Grawitz tumor; Inhibition; Class I histocompatibility antigen; Biological receptor
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.11321

Among tumor‐infiltrating lymphocytes (TILs) directly isolated from renal cell carcinomas (RCCs), we found substantial numbers of natural killer (NK) cells in most tumor tissues. They could be identified reliably in situ with an antibody directed against the activating receptor (AR) NKp46 that is exclusively expressed by all NK cells. NK‐enriched TILs (NK‐TILs) showed cytotoxicity against major histocompatibility complex (MHC) class I‐negative cell lines. The ability to detect lysis of target cells was dependent on the percentage of NK cells within the TILs, and cytotoxicity was only observed after overnight activation with low‐dose interleukin‐2 (IL‐2). Infiltrating NK cells were found to express various inhibitory receptors (IRs); among these the CD94/NKG2A receptor complex was overrepresented compared to the autologous peripheral blood mononuclear cell (PBMC) population. Other IRs were underrepresented, indicating that NK subpopulations vary in their tumor‐infiltrating capacity. IRs expressed by NK‐TILs are functional since receptor engagement with MHC class I ligands presented by human leukocyte antigen (HLA)‐transfected target cell lines was able to inhibit NK‐mediated cytotoxicity. NK‐TILs were also able to lyse autologous or allogeneic tumor cell lines in vitro. This activity correlated with low HLA class I surface expression since lysis could be inhibited by interferon (IFN)‐γ‐expressing RCC transductants that displayed a higher surface density of HLA class I molecules. Therefore, NK cells infiltrating tumor tissues have an inherent ability to recognize transformed cells, but they require cytokine activation and are sensitive to inhibition by IR ligands. © 2003 Wiley‐Liss, Inc.